A form of inflammatory bowel disease, ulcerative colitis has many established treatments, with a number of new ones in development.
There are two major forms of inflammatory bowel disease (IBD): Crohn’s disease (CD) and ulcerative colitis (UC). As of 2004, IBD affected between one and two million people in the United States with an incidence of 70 to 150 cases per 100,000 individuals.1,2 Some epidemiology studies suggest a 46 percent rise in prevalence of IBD from 2006 to 2021.3 This is paramount since UC can lead to significant morbidity and mortality among a wide spectrum of the population.
What Is UC?
UC is an idiopathic inflammatory disorder of the colonic mucosa (the inner lining of the colon and rectum) that is characterized by superficial mucosal intestinal inflammation that extends in a contiguous fashion. There are four classic descriptions that are dependent on the location involved, including:
- Ulcerative proctitis, which involves the rectum only
- Ulcerative proctosigmoiditis, which involves the rectum to the sigmoid (the lower part of the colon near the sigmoid colon)
- Distal or left-sided UC, which involves the rectum to the splenic flexure (the bend where the transverse colon and descending colon meet in the upper left part of the abdomen)
- Pancolitis, which involves the rectum to the rest of the colon, past the flexure
Causes of UC
UC is usually seen in a bimodal age distribution with patients presenting between 20 and 30 years and 60 and 70 years of age. Interestingly, the risk of UC is increased among those who smoke, take oral contraceptives and, possibly, those who have had antibiotic exposure in childhood (especially anti-anaerobic antibiotics). Significant research has been completed and is ongoing regarding the contributions of the intestinal microbiome as a cause of IBD, but this remains to be established. Some research suggests statins (i.e., atorvastatin) could potentially decrease the risk of IBD.
UC is usually seen in a bimodal age distribution with patients presenting between 20 and 30 years and 60 and 70 years of age.
Symptoms and Progression of UC
The classic symptoms seen with UC include change in bowel habits, hematochezia (rectal bleeding), tenesmus (frequent urge to go to the bathroom without being able to go), nocturnal stools and fecal urgency. In contrast, patients with proctitis or proctosigmoiditis can present with constipation. However, these symptoms listed are variable, and 80 percent of patients will have flares or intermittent attacks of their disease over weeks to years. Approximately five to 10 percent of patients will present with an initial severe or fulminant (sudden and severe) presentation requiring colectomy (a surgical procedure to remove all or part of the colon). However, with new medications, this is becoming less frequent. Unfortunately, only one percent of patients has a relapse-free course following their initial diagnosis.
Diagnosing UC
Clinical. There are many differential diagnoses to consider when a patient first presents with symptoms of UC. On physical examination, individuals may present along a spectrum of a normal abdominal exam to severe diffuse tenderness, along with pallor (unhealthy pale appearance), dehydration, tachycardia (a heart rate over 100 beats a minute) and/or fever. The first step toward diagnosis is to rule out infectious etiologies such as bacteria (Clostridioides difficile, Escherichia coli, Salmonella, Campylobacter, Yersinia, etc.), parasites (amebiasis, chlamydia, schistosomiasis) and viral (cytomegalovirus, herpes simplex, adenovirus) causes.
Patients should undergo laboratory evaluation with CBC, CMP, C-reactive protein and fecal calprotectin. Endoscopic evaluation with a colonoscopy should then be pursued to rule out other noninfectious causes such as microscopic colitis, segmental colitis associated with diverticulosis, ischemic colitis, medication-induced enterocolitis and malignancies.
With UC, the mucosa and submucosa are involved classically in a continuous fashion. The mucosa are erythematous (exhibiting abnormal redness of the skin or mucous membranes due to the accumulation of blood in dilated capillaries) and friable (tissue that is easily irritated, which makes it more prone to inflammation, bleeding or tearing), and different endoscopic scoring systems, including the Mayo Score Disease Activity Index (Table 1)4 or the Ulcerative Colitis Endoscopic Index of Severity (UCEIS) (Table 2),5 allow the endoscopists to grade these from normal to severe disease. Additionally, these scoring systems are used to evaluate disease status and response to therapy on repeat future endoscopic evaluation. In summary, endoscopy is performed to determine the extent of disease, severity of disease, confirmation of disease and presence of complications (dysplasia, viruses and cancer).
Pathology. The biopsies of UC in early disease show cryptitis (the presence of inflammation in the crypts [small tubular glands, pits or recesses] of the small or large intestine when viewed under a microscope) with discharge of mucus from goblet cells and increased epithelial cell turnover. This then progresses to crypt architecture distortion (one of the diagnostic hallmarks in the diagnosis of IBD against other forms of colitis), crypt atrophy (a loss of tissue compared to normal), inter-crypt spacing, irregular mucosal (the thin skin that covers the inside surface of parts of the body such as the nose and mouth and produces mucus to protect them) surface, basal lymphoid aggregates and, finally, chronic inflammatory infiltrate. In long-standing disease, the mucosa appears atrophied with loss and shortening of crypts, decreased goblet cells and presence of Paneth cell metaplasia.
Table 1. Mayo Score Disease Activity Index
| Stool Frequency | Rectal Bleeding | Mucosal Appearance at Endoscopy | Physician Rating of Disease Activity | |
|---|---|---|---|---|
| 0 Points | Normal | None | Normal or inactive disease | Normal |
| 1 Point | 1-2 stools a day more than normal | Visible blood with stool less than half the time | Mild disease (erythema, decreased vascular pattern, mild friability) | Mild |
| 2 Points | 3-4 stools a day more than normal | Visible blood with stool half of the time or more | Moderate disease (marked erythema, absent vascular pattern, friability, erosions) | Moderate |
| 3 Points | >4 stools a day more than normal | Passing blood alone | Severe disease (spontaneous bleeding, ulceration) | Severe |
Table 2. Ulcerative Colitis Endoscopic Index of Severity (UCEIS)
| Vascular Pattern | Bleeding | Erosions and Ulcers | |
|---|---|---|---|
| 0 Points | Normal | None (no visible blood) | None (normal mucosa, no visible erosions or ulcers) |
| 1 Point | Patchy obliteration | Mucosal (some spots of streaks of coagulated blood on the surface of the mucosa ahead of the scope that can be washed away) | Erosions (tiny 5mm defects in the mucosa of a white or yellow color with a flat edge) |
| 2 Points | Obliterated | Luminal mild (some free liquid blood in the lumen) | Supericial ulcer (larger >5mm defects in the mucosa that are discrete ibrin-covered ulcers when compared with erosions but remain supericial) |
| 3 Points | Bleeding | Luminal moderate or severe (frank blood in the lumen ahead of the endoscope or visibly oozing from a hemorrhagic mucosa) | Deep ulcer (deeper excavated defects in the mucosa with slightly raised edge) |
Treating UC
Treatments for UC can be classified into steroids (either prednisone or budesonide), disease-modifying anti-rheumatic drugs (DMARDS), biologics and small molecule drugs. DMARDs include 5-aminosalicylic acid suppositories, enemas and oral formulations such as sulfasalazine or mesalamine. These medications are recommended for use in patients with mild disease or with disease confined to the sigmoid or rectum. Multiple biologics have been approved to treat UC. These medications have a variety of different mechanism of actions (tumor necrosis factor alpha [TNF-a], interleukin-12 and -23 [IL-12 and IL-23], Integrin α4β7), administration methods and safety profiles. Most of these medications include either infusions, injections or a combination of both. Newer to the treatment landscape for UC are small molecule medications that are all currently taken via oral administration (Janus kinase inhibitors [JAKs], sphingosine-1-phosphate [S1P]). These medications are outlined in Table 3.
Table 3. Biologic and Small Molecule Treatments for Ulcerative Colitis
| Medication | Mechanism of Action | Administration Routes | Safety Profile |
|---|---|---|---|
| Infliximab | Tumor necrosis factor-alpha | Intravenous | Increased risk of infections, malignancies, congestive heart failure, infusion reactions |
| Adalimumab | Tumor necrosis factor-alpha | Subcutaneous | Increased risk of infections, malignancies, congestive heart failure, injection site reactions |
| Vedolizumab | Integrin α4β7 | Intravenous | One case of progressive multifocal leukoencephalopathy (PML) |
| Ustekinumab | Interleukin-12 and interleukin-23 | Subcutaneous | Non-melanoma skin cancers |
| Tofacitinib | Non-selective Janus kinase inhibitor | Oral | Increased risk of infections, cardiovascular disease, thrombosis, malignancies |
| Ozanimod | Sphingosine-1-phosphate | Oral | Increased risk of infections, PML, macular edema, arrhythmias, posterior reversible encephalopathy syndrome |
| Upadacitinib | Selective Janus kinase inhibitor | Oral | Increased risk of infections, cardiovascular disease, thrombosis, malignancies |
Current Research
Several new drugs are being studied in clinical trials for UC. Many of these have similar mechanisms of action as currently accepted treatments, while others have new mechanisms of action. Currently, according to the Crohn’s & Colitis Foundation website, it is reported that there are 241 Phase I, II and III clinical trials recruiting related to UC.6 For TNF-a, there are investigational drugs such as AVX-470, OPRX-106 and V565 in oral formulations compared to those current intravenous and subcutaneous formulations. Vedolizumab has an injectable subcutaneous formulation that will be a self-injection every two weeks, hopefully coming to market soon. Additionally, there are several anti-IL-23 drugs such as mirikizumab, guselkumab, JAK-1 selective inhibitor filgotinib and JAK-2 selective inhibitor deucravacitinib. Furthermore, there is a new S1P drug, etrasimod, pending U.S. Food and Drug Administration approval. Regarding new mechanism of action medications for UC, there are trials ongoing for tumor necrosis factor like ligand 1a drugs (anti TL1a) such as PF-06480605, , toll-like receptor (TLR9) activators such as cobitolimod and microRNA-124 (miR-124) up regulator obefazimod.10,11
Looking Ahead
Many aspects of diagnosis and treatment of UC remain to be identified and addressed. These include noninvasive detection and monitoring of treatment response, prevention of postoperative septic complications and mucosal targeted drug delivery systems. A large unmet need currently is the lack of individual, patient-specific, targeted therapies; this could perhaps be addressed by the presence or absence of drug-specific or genetic biomarkers predetermining the likelihood of response to the separate drug mechanisms of action. There are hopes for use of artificial intelligence for identification of dysplasia (the presence of cells of an abnormal type within a tissue, which may signify a stage preceding the development of cancer) during colonoscopy, decreasing the development of malignancy. These hopeful future developments will allow better outcomes for patients and decreased need for surgical resection, development in colorectal cancer and overall mortality.
References
- Loftus, EV Jr. Clinical Epidemiology of Inflammatory Bowel Disease: Incidence, Prevalence, and Environmental Influences. Gastroenterology, 2004 May;126(6):1504-17. Accessed at www.gastrojournal.org/article/S0016-5085(04)00462-7/fulltext.
- Molodecky, NA, Soon, IS, Rabi, DM, et al. Increasing Incidence and Prevalence of the Inflammatory Bowel Diseases with Time, Based on Systematic Review. Gastroenterology, 2012 Jan;142(1):46-54.e42; quiz e30. Accessed at www.gastrojournal.org/article/S0016-5085(11)01378-3/fulltext.
- Caviglia, GP, Garrone, A, Bertolino, C, et al. Epidemiology of Inflammatory Bowel Diseases: A Population Study in a Healthcare District of North-West Italy. Journal of Clinical Medicine, 2023 Jan 13;12(2):641. Accessed at www.ncbi.nlm.nih.gov/pmc/articles/PMC9860659.
- Schroeder, KW, Tremaine, WJ, and Ilstrup, DM. Coated Oral 5-Aminosalicylic Acid Therapy for Mildly to Moderately Active Ulcerative Colitis. A Randomized Study. New England Journal of Medicine, 1987 Dec 24;317(26):1625-9. Accessed at pubmed.ncbi.nlm.nih.gov/3317057.
- Ikeya, K, Hanai, H, Sugimoto, K, et al. The Ulcerative Colitis Endoscopic Index of Severity More Accurately Reflects Clinical Outcomes and Long-Term Prognosis than the Mayo Endoscopic Score. Journal of Crohn’s and Colitis, 2016 Mar;10(3):286-95. Accessed at pubmed.ncbi.nlm.nih.gov/26581895.
- Clinical Trial Finder. Crohn’s & Colitis Foundation. Accessed at trials.crohnscolitisfoundation.org.
Danese, S, Klopocka, M, Scherl, EJ, et al. Anti-TL1A Antibody PF-06480605 Safety and Efficacy for Ulcerative Colitis: A Phase 2a Single-Arm Study. Clinical Gastroenterology and Hepatology, 2021 Nov;19(11):2324-2332.e6. Accessed at pubmed.ncbi.nlm.nih.gov/34126262. - Hassan-Zahraee, M, Ye, Z, Xi, L, et al. Antitumor Necrosis Factor-like Ligand 1A Therapy Targets Tissue Inflammation and Fibrosis Pathways and Reduces Gut Pathobionts in Ulcerative Colitis. Inflammatory Bowel Disease, 2022 Mar 2;28(3):434-446. Accessed at academic.oup.com/ibdjournal/article/28/3/434/6357022.
- Atreya, R, Peyrin-Biroulet, L, Klymenko, A, et al. Cobitolimod for Moderate-to-Severe, Left-Sided Ulcerative Colitis (CONDUCT): A Phase 2b Randomised, Double-Blind, Placebo-Controlled, Dose-Ranging Induction Trial. Lancet Gastroenterology and Hepatology, 2020 Dec;5(12):1063-1075. Accessed at pubmed.ncbi.nlm.nih.gov/33031757.
- Vermeire, S, Sands, BE, Tilg, H, et al. ABX464 (Obefazimod) for Moderate-to-Severe, Active Ulcerative Colitis: A Phase 2b, Double-Blind, Randomised, Placebo-Controlled Induction Trial and 48 Week, Open-Label Extension. Lancet Gastroenterology and Hepatology, 2022 Nov;7(11):1024-1035. Accessed at pubmed.ncbi.nlm.nih.gov/36075249.
- Zurba, Y, Gros, B, and Shehab, M. Exploring the Pipeline of Novel Therapies for Inflammatory Bowel Disease; State of the Art Review. Biomedicines, 2023 Mar 1;11(3):747. Accessed at www.ncbi.nlm.nih.gov/pmc/articles/PMC10045261.
- Dhyani, M, Joshi, N, Bemelman, WA, et al. Challenges in IBD Research: Novel Technologies. Inflammatory Bowel Disease, 2019 May 16;25(Suppl 2):S24-S30. Accessed at pubmed.ncbi.nlm.nih.gov/31095703.
